a Eppley Institute , University of Nebraska Medical Center , Omaha , NE , USA.
b Fred & Pamela Buffett Cancer Center , University of Nebraska Medical Center , Omaha , NE , USA.
Epigenetics. 2019 Feb;14(2):185-197. doi: 10.1080/15592294.2019.1581590. Epub 2019 Mar 4.
The POTE gene family consists of 14 homologous genes localized to autosomal pericentromeres, and a sub-set of POTEs are cancer-testis antigen (CTA) genes. POTEs are over-expressed in epithelial ovarian cancer (EOC), including the high-grade serous subtype (HGSC), and expression of individual POTEs correlates with chemoresistance and reduced survival in HGSC. The mechanisms driving POTE overexpression in EOC and other cancers is unknown. Here, we investigated the role of epigenetics in regulating POTE expression, with a focus on DNA hypomethylation. Consistent with their pericentromeric localization, Pan-POTE expression in EOC correlated with expression of the pericentromeric repeat NBL2, which was not the case for non-pericentromeric CTAs. POTE genomic regions contain LINE-1 (L1) sequences, and Pan-POTE expression correlated with both global and POTE-specific L1 hypomethylation in EOC. Analysis of individual POTEs using RNA-seq and DNA methylome data from fallopian tube epithelia (FTE) and HGSC revealed that POTEs C, E, and F have increased expression in HGSC in conjunction with DNA hypomethylation at 5' promoter or enhancer regions. Moreover, POTEs C/E/F showed additional increased expression in recurrent HGSC in conjunction with 5' hypomethylation, using patient-matched samples. Experiments using decitabine treatment and DNMT knockout cell lines verified a functional contribution of DNA methylation to POTE repression, and epigenetic drug combinations targeting histone deacetylases (HDACs) and histone methyltransferases (HMTs) in combination with decitabine further increased POTE expression. In summary, several alterations of the cancer epigenome, including pericentromeric activation, global and locus-specific L1 hypomethylation, and locus-specific 5' CpG hypomethylation, converge to promote POTE expression in ovarian cancer.
POTE 基因家族由 14 个位于常染色体着丝粒周围的同源基因组成，其中一部分 POTEs 是癌症睾丸抗原（CTA）基因。POTEs 在卵巢上皮癌（EOC）中过度表达，包括高级别浆液性亚型（HGSC），并且个别 POTEs 的表达与 HGSC 中的化疗耐药和生存时间缩短相关。导致 EOC 和其他癌症中 POTE 过度表达的机制尚不清楚。在这里，我们研究了表观遗传学在调节 POTE 表达中的作用，重点是 DNA 低甲基化。与它们位于着丝粒周围的位置一致，EOC 中的泛 POTE 表达与着丝粒周围重复 NBL2 的表达相关，而非着丝粒 CTA 则不是这种情况。POTE 基因组区域包含 LINE-1（L1）序列，并且泛 POTE 表达与 EOC 中的全局和 POTE 特异性 L1 低甲基化相关。使用来自输卵管上皮（FTE）和 HGSC 的 RNA-seq 和 DNA 甲基化组数据对个别 POTEs 进行分析，结果表明，在与 5'启动子或增强子区域的 DNA 低甲基化相结合的情况下，POTEs C、E 和 F 在 HGSC 中表达增加。此外，使用患者匹配样本，在复发性 HGSC 中，POTEs C/E/F 还显示出与 5'低甲基化相关的额外表达增加。使用地西他滨治疗和 DNMT 敲除细胞系的实验验证了 DNA 甲基化对 POTE 抑制的功能贡献，并且针对组蛋白去乙酰化酶（HDACs）和组蛋白甲基转移酶（HMTs）的表观遗传药物组合与地西他滨联合使用进一步增加了 POTE 的表达。总之，癌症表观基因组的几种改变，包括着丝粒周围激活、全局和局部 L1 低甲基化以及局部 5'CpG 低甲基化，共同促进了卵巢癌中 POTE 的表达。
